The ‘Galilean Style in Science’ and the Inconsistency of Linguistic Theorising

Chomsky’s principle of epistemological tolerance says that in theoretical linguistics contradictions between the data and the hypotheses may be temporarily tolerated in order to protect the explanatory power of the theory. The paper raises the following problem: What kinds of contradictions may be tolerated between the data and the hypotheses in theoretical linguistics? First a model of paraconsistent logic is introduced which differentiates between week and strong contradiction. As a second step, a case study is carried out which exemplifies that the principle of epistemological tolerance may be interpreted as the tolerance of week contradiction. The third step of the argumentation focuses on another case study which exemplifies that the principle of epistemological tolerance must not be interpreted as the tolerance of strong contradiction. The reason for the latter insight is the unreliability and the uncertainty of introspective data. From this finding the author draws the conclusion that it is the integration of different data types that may lead to the improvement of current theoretical linguistics and that the integration of different data types requires a novel methodology which, for the time being, is not available

The ‘Galilean Style in Science’ and the Inconsistency of Linguistic Theorising

Chomsky’s principle of epistemological tolerance says that in theoretical linguistics contradictions between the data and the hypotheses may be temporarily tolerated in order to protect the explanatory power of the theory. The paper raises the following problem: What kinds of contradictions may be tolerated between the data and the hypotheses in theoretical linguistics? First a model of paraconsistent logic is introduced which differentiates between week and strong contradiction. As a second step, a case study is carried out which exemplifies that the principle of epistemological tolerance may be interpreted as the tolerance of week contradiction. The third step of the argumentation focuses on another case study which exemplifies that the principle of epistemological tolerance must not be interpreted as the tolerance of strong contradiction. The reason for the latter insight is the unreliability and the uncertainty of introspective data. From this finding the author draws the conclusion that it is the integration of different data types that may lead to the improvement of current theoretical linguistics and that the integration of different data types requires a novel methodology which, for the time being, is not available

Acetylation of C-terminal lysines modulates protein turnover and stability of Connexin-32

Background The gap junction protein, Connexin32 (Cx32), is expressed in various tissues including liver, exocrine pancreas, gastrointestinal epithelium, and the glia of the central and peripheral nervous system. Gap junction-mediated cell-cell communication and channel-independent processes of Cx32 contribute to the regulation of physiological and cellular activities such as glial differentiation, survival, and proliferation; maintenance of the hepatic epithelium; and axonal myelination. Mutations in Cx32 cause X-linked Charcot–Marie–Tooth disease (CMT1X), an inherited peripheral neuropathy. Several CMT1X causing mutations are found in the cytoplasmic domains of Cx32, a region implicated in the regulation of gap junction assembly, turnover and function. Here we investigate the roles of acetylation and ubiquitination in the C-terminus on Cx32 protein function. Cx32 protein turnover, ubiquitination, and response to deacetylase inhibitors were determined for wild-type and C-terminus lysine mutants using transiently transfected Neuro2A (N2a) cells. Results We report here that Cx32 is acetylated in transfected N2a cells and that inhibition of the histone deacetylase, HDAC6, results in an accumulation of Cx32. We identified five lysine acetylation targets in the C-terminus. Mutational analysis demonstrates that these lysines are involved in the regulation of Cx32 ubiquitination and turnover. While these lysines are not required for functional Cx32 mediated cell-cell communication, BrdU incorporation studies demonstrate that their relative acetylation state plays a channel-independent role in Cx32-mediated control of cell proliferation. Conclusion Taken together these results highlight the role of post translational modifications and lysines in the C-terminal tail of Cx32 in the fine-tuning of Cx32 protein stability and channel-independent functions

Treatment response in rheumatoid arthritis is predicted by the microbiome: a large observational study in UK DMARD-naïve patients.

OBJECTIVES: Disease-modifying antirheumatic drugs (DMARDs) are first line treatment in rheumatoid arthritis (RA). Treatment response to DMARDs is patient-specific, dose efficacy is difficult to predict and long-term results variable. The gut microbiota are known to play a pivotal role in prodromal and early-disease RA, manifested by Prevotella spp. enrichment. The clinical response to therapy may be mediated by microbiota, and large-scale studies assessing the microbiome are few. This study assessed whether microbiome signals were associated with, and predictive of, patient response to DMARD-treatment. Accurate early identification of those who will respond poorly to DMARD therapy would allow selection of alternative treatment (e.g. biologic therapy), and potentially improve patient outcome. METHODS: A multicentre, longitudinal, observational study of stool- and saliva microbiome was performed in DMARD-naïve, newly diagnosed RA patients during introduction of DMARD treatment. Clinical data and samples were collected at baseline (n = 144) in DMARD-naïve patients and at six weeks (n = 117) and 12 weeks (n = 95) into DMARD-therapy. Samples collected (n = 365 stool, n = 365 saliva) underwent shotgun sequencing. Disease activity measures were collected at each timepoint and minimal clinically important improvement determined. RESULTS: In total, 26 stool microbes were found to decrease in those manifesting a minimal clinically important improvement. Prevotella spp. and Streptococcus spp. were the predominant taxa to decline following six weeks and 12 weeks of DMARDs, respectively. Furthermore, baseline microbiota of DMARD-naïve patients were indicative of future response. CONCLUSION: DMARDs appear to restore a perturbed microbiome to a eubiotic state. Moreover, microbiome status can be used to predict likelihood of patient response to DMARD

No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins.

INTRODUCTION: Intervertebral disc degeneration and Modic change are the main spinal structural changes associated with chronic low back pain (LBP). Both conditions are thought to manifest local inflammation and if inflammatory proteins translocate to the blood circulation could be detected systemically. The work here assesses whether the presence of disc degeneration is associated with detectable blood level changes of five inflammatory markers and whether chronic LBP is associated with these changes. MATERIALS AND METHODS: Two hundred and forty TwinsUK cohort participants with both MRI disc degeneration grade and Modic change extent, and IL-6, IL-8, IL-8 TNF, and CX3CL1 protein blood concentration measurements were included in this work. Linear mixed effects models were used to test the association of blood cytokine concentration with disc degeneration score and Modic change volumetric score. Association of chronic LBP status from questionnaires with disc degeneration, Modic change, and cytokine blood concentration was also tested. RESULTS: No statistically significant association between disc degeneration or Modic change with cytokine blood concentration was found. Instead, regression analysis pointed strong association between cytokine blood concentration with body mass index for IL-6 and with age for IL-6 and TNF. Mild association was found between IL-8 blood concentration and body mass index. Additionally, LBP status was associated with Modic change volumetric score but not associated with any cytokine concentration. CONCLUSIONS: We found no evidence that Modic change and disc degeneration are able to produce changes in tested blood cytokine concentration. However, age and body mass index have strong influence on cytokine concentration and both are associated with the conditions studied which may confound associations found in the literature. It is then unlikely that cytokines produced in the disc or vertebral bone marrow induce chronic LBP

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of ’urban hotspots’. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of ’urban hotspots’. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors

Index estimates for free boundary minimal hypersurfaces

We show that the Morse index of a properly embedded free boundary minimal hypersurface in a strictly mean convex domain of the Euclidean space grows linearly with the dimension of its first relative homology group (which is at least as big as the number of its boundary components, minus one). In ambient dimension three, this implies a lower bound for the index of a free boundary minimal surface which is linear both with respect to the genus and the number of boundary components. Thereby, the compactness theorem by Fraser and Li implies a strong compactness theorem for the space of free boundary minimal surfaces with uniformly bounded Morse index inside a convex domain. Our estimates also imply that the examples constructed, in the unit ball, by Fraser–Schoen and Folha–Pacard–Zolotareva have arbitrarily large index. Extensions of our results to more general settings (including various classes of positively curved Riemannian manifolds and other convexity assumptions) are discussed

Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low-dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti-TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization